The goal of this project is to develop a novel inhibitor of methane formation in ruminant animals. Currently, monensin, a relatively nonspecific antibiotic, is widely used in the livestock industry. Monensin increases agricultural productivity by decreasing methane and increasing propionate production; however, it also inhibits acetogenesis, which is a beneficial process for the animal. We will target a specific biosynthetic enzyme that catalyzes an essential step for survival of methanogenic microbes, which are members of the kingdom Archaea, yet is not present in eukaryotes or bacteria. A specific methanogenesis inhibitor would have the benefits of monensin on increased productivity without the detrimental effect of antibiotic use. It should have significant market value. The immediate projected use would be on feedlot cattle, pigs, and sheep. Such an inhibitor could also be used to decrease methane production in the human GI tract. Since domesticated livestock is the largest global source of methane, inhibiting methanogenesis by ruminant animals has the potential of mitigating the greenhouse effect. Our plan is to synthesize and characterize inhibitors of the biosynthetic enzyme that arrest methanogenesis at a concentration below 100 nanomolar.